Vascular endothelial growth factor (VEGF) is a cytokine involved in angiogenesis. The ligand VEGF-A interacts with VEGF receptor-1 (VEGFR1) and VEGFR2, thereby initiating an angiogenesis signaling pathway in normal and tumor vasculature. Antagonists of VEGF are known to be useful for the treatment of a variety of diseases and disorders including cancers, eye diseases and other conditions involving excessive, unwanted or inappropriate angiogenesis. An example of a VEGF antagonist is aflibercept (also known as VEGF Trap; or ziv-aflibercept, which is marketed as ZALTRAP®, Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.). Aflibercept is a VEGF receptor-based chimeric molecule comprising domain 2 from VEGFR1 fused to domain 3 from VEGFR2, which is, in turn, attached through the hinge region to the Fc(a) domain of human IgG1. Ziv-aflibercept is approved for the treatment of metastatic colorectal cancer and is being developed for the treatment of other cancerous conditions as well. VEGF Trap is described, e.g., in U.S. Pat. No. 7,070,959; see also, Holash et al., Proc. Natl. Acad. Sci. USA 99:11393-11398 (2002).
To date, no predictive biomarkers of resistance or susceptibility to VEGF inhibition have been validated. Although VEGF antagonists have shown great promise in the treatment of cancer, validated biomarkers that predict the efficacy of anti-VEGF therapy are needed for the effective identification and selection of patient sub-populations that respond favorably to anti-VEGF therapy. Accordingly, an unmet need exists in the art for identifying and validating predictive and prognostic biomarkers in patients with metastatic cancer who are administered anti-VEGF therapy.